WO2004040296A1 - Reactifs servant a mesurer des peroxynitrites - Google Patents

Reactifs servant a mesurer des peroxynitrites Download PDF

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Publication number
WO2004040296A1
WO2004040296A1 PCT/JP2003/013179 JP0313179W WO2004040296A1 WO 2004040296 A1 WO2004040296 A1 WO 2004040296A1 JP 0313179 W JP0313179 W JP 0313179W WO 2004040296 A1 WO2004040296 A1 WO 2004040296A1
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WO
WIPO (PCT)
Prior art keywords
peroxynitrite
salt
general formula
measuring
compound
Prior art date
Application number
PCT/JP2003/013179
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English (en)
Japanese (ja)
Inventor
Tetsuo Nagano
Ken-Ichi Setsukinai
Yasuteru Urano
Original Assignee
Daiichi Pure Chemicals Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Pure Chemicals Co., Ltd. filed Critical Daiichi Pure Chemicals Co., Ltd.
Priority to EP03758728A priority Critical patent/EP1553409A1/fr
Priority to AU2003275553A priority patent/AU2003275553A1/en
Priority to US10/531,664 priority patent/US20060211122A1/en
Priority to JP2004548020A priority patent/JP4206381B2/ja
Publication of WO2004040296A1 publication Critical patent/WO2004040296A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
    • G01N31/22—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators
    • G01N31/227—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators for nitrates or nitrites
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1003—Carbocyclic compounds
    • C09K2211/1011—Condensed systems
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1022—Heterocyclic compounds bridged by heteroatoms, e.g. N, P, Si or B
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/17—Nitrogen containing
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/17—Nitrogen containing
    • Y10T436/173076—Nitrite or nitrate

Definitions

  • the present invention relates to a reagent for measuring peroxynitrite.
  • Nitric oxide is a vasorelaxant, regulates neuronal communication, regulates cell death,
  • Peroxynitrite is a representative of RNS and is produced by the reaction of NO with superoxide. The rate of this production reaction is almost diffusion-controlled, and when superoxide generated by NADPH oxidase and NO generated by NO synthase (NOS) coexist, ONOCT force is quickly generated.
  • ONOCr has a high oxidizing ability, such as the ability to hydroxylate aromatic rings, and has a characteristic reactivity, such as efficient nitration of tyrosine. Recent reports indicate that nitration of tyrosine inhibits tyrosine phosphorylation and has important effects on signaling such as MAPK and PI3 / Akt cascade.
  • ONOO- detection method developed so far (1) a method in which tyrosine is stained with antibody against nitrotyrosine to generate is nitrated, (2) ONOO- be reacted with H 2 0 2 Method to detect singlet oxygen generated by luminescence at 1.3 ⁇ m. It is. Although the method (1) has high specificity and is widely used, there is a problem in that it cannot be applied to a live cell system to detect ONOO- in real time because of antibody staining.
  • a chemiluminescence method using luminol and (4) a fluorescence detection method using a fluorescent probe that detects reactive oxygen species in general, such as 2,2,7'-dichlorodihydrofluorescein (DCFH) Is also used.
  • DCFH 2,2,7'-dichlorodihydrofluorescein
  • these methods do not provide reliable detection even when various inhibitors with very specificity are used.
  • DCFH also reacts with NO and superoxide, and an increase in fluorescence is observed. Therefore, it is necessary to distinguish between the power of detecting ONOO- and the detection of NO or superoxide. Is impossible.
  • An object of the present invention is to provide a means for specifically detecting peroxynitrite.
  • the present invention provides a reagent for measuring peroxynitrite, which does not react with NO and superoxide, which are precursors of peroxynitrite, but can react specifically with peroxynitrite. This is the subject of the present invention.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the compound represented by the following general formula (I) has the above-mentioned properties, and is unique to peroxynitrite.
  • the present invention was found to be useful as a selective detection reagent, and the present invention was completed.
  • R 1 represents a substituted or unsubstituted amino group or hydroxy group
  • R 2 represents a 2-carboxyphenyl group which may have a substituent
  • X 1 and X 2 each independently represent A hydrogen atom or a halogen atom
  • the reagent for measurement described above is provided which is phenoxy-3H-xanthen-3-one-9-yl] benzoic acid.
  • the present invention relates to a method for measuring peroxynitrite, comprising the following steps: (A) reacting a compound represented by the above general formula (I) or a salt thereof with peroxynitrite. And (B) measuring the fluorescence of the dephenylated compound produced in the above step (A) (compound in which the phenyl group substituted by R 1 in the above general formula (I) is replaced by a hydrogen atom) or a salt thereof.
  • a method comprising the steps is provided.
  • the present invention provides the use of the compound represented by the above general formula (I) for the production of the above-mentioned reagent for measuring peroxynitrite.
  • R 1 represents a substituted or unsubstituted amino group or hydroxy group.
  • substituent on the amino group include a C ⁇ alkyl group such as a methyl group and an ethyl group (the alkyl group may be any of linear, branched, cyclic, or a combination thereof), a benzyl group And an aralkyl group such as a phenyl group, but are not limited thereto. Two substituents on amino group If so, they may be the same or different.
  • the amino group is preferably unsubstituted.
  • the substitution position of the amino group or the hydroxy group represented by R 1 is not particularly limited, but is preferably a para position.
  • R 2 represents a 2-carboxyphenyl group which may have a substituent, and is preferably an unsubstituted 2-carboxyphenyl group.
  • X 1 and X 2 each independently represent a hydrogen atom or a halogen atom, but it is preferable that X 1 and X 2 are hydrogen atoms.
  • X 1 and X 2 are a halogen atom, they may be the same or different, but for example, a fluorine atom, a chlorine atom and the like are preferably used.
  • the kind of the salt of the above general formula (I) is not particularly limited, but it can be used as a measuring reagent of the present invention such as a base addition salt, an acid addition salt and an amino acid salt.
  • the base addition salt include metal salts such as sodium salt, potassium salt, calcium salt and magnesium salt, ammonium salts, and organic amine salts such as triethylamine salt, piperidine salt and morpholine salt.
  • the addition salt include mineral salts such as hydrochloride, sulfate and nitrate, and organic acid salts such as methanesulfonate, paratoluenesulfonate, citrate and oxalate. it can.
  • the amino acid salt include a glycine salt.
  • physiologically acceptable water-soluble salts can be suitably used in the measuring reagent and the measuring method of the present invention.
  • the compound represented by the general formula (I) or a salt thereof in a free form may exist as a hydrate or a solvate, but the hydrate or the solvate is used for the measurement of the present invention. It may be used as a reagent.
  • the type of the solvent that forms the solvate is not particularly limited, and examples thereof include solvents such as ethanol, acetone, and isopropanol.
  • the compound represented by the general formula (I) may have one or more asymmetric carbon atoms depending on the type of the substituent, and Stereoisomers, such as stereoisomers or diastereoisomers, may exist. Pure forms of stereoisomers, arbitrary mixtures of stereoisomers, racemates and the like may be used as the measuring reagent of the present invention. Further, the compound represented by the general formula (I) may form a rataton ring in the molecule, and a compound having a rataton ring is also included in the scope of the present invention. It goes without saying that it is included in the box. Further, the optically active substance based on the rataton formation is also included in the scope of the present invention.
  • the compound represented by the general formula (I) can be easily obtained by the method described in International Publication WO 01/64664.
  • xanthen-3-on-9-yl] benzoic acid hereinafter, sometimes referred to as HPF
  • p-a5 a compound that is a nophenyl group (2- [6- (4'-amino) phenoxy) -3H-xanthen-3-on-9-yl] benzoic acid: hereinafter may be referred to as APF in the present specification), which are specifically referred to as ss_lF and ss-3F, respectively.
  • the compound represented by the above general formula (I) or a salt thereof reacts with peroxynitrite under mild conditions, for example, under physiological conditions, and reacts with peroxynitrite to form a fluorinated compound which is a dephenylated product (in general formula ⁇ ).
  • R 1 is a compound in which the phenyl group to be substituted is replaced by a hydrogen atom) or a salt thereof.
  • the compound represented by the general formula (I) or a salt thereof is substantially non-fluorescent, while a defluorinated fluorescein compound or a salt thereof has a property of emitting high intensity fluorescence. I have. Therefore, after reacting the compound represented by the above formula (I) or a salt thereof with peroxynitrite, the fluorescence of the dephenylated compound or a salt thereof is measured to obtain peroxynitrite. Light can be measured with high sensitivity.
  • the compound represented by the above general formula (I) or a salt thereof has a feature that it has substantially no reactivity with NO or superoxide, which is a precursor of peroxynitrite, under the above conditions. There is. Therefore, by using the compound represented by the above general formula (I) or a salt thereof, it is possible to specifically measure only peroxynitrite under physiological conditions without the influence of NO or superoxide. It is. For example, by using the compound represented by the general formula (I) or a salt thereof as a measuring reagent, peroxynitrite localized in individual cells or specific tissues can be accurately and simply measured.
  • the term "measurement” as used herein should be interpreted in the broadest sense, including measurement, testing, detection, etc., performed for quantitative, qualitative, or diagnostic purposes.
  • the method for measuring peroxynitrite according to the present invention generally comprises (A) reacting a compound represented by the above general formula (I) or a salt thereof with peroxynitrite, and (B) Fluorescence of the dephenyl compound produced in the above step (A) (corresponding to a compound in which the phenyl group substituted by R 1 in the above general formula (I) is replaced by a hydrogen atom) or a salt thereof is measured Including the step of:
  • the fluorescence of the dephenylated compound or a salt thereof can be measured by a conventional method, and a method of measuring a fluorescence spectrum in vitro or a method of measuring a fluorescence spectrum in vivo using a bioimaging technique is used. Etc. can be adopted. For example, when performing quantification, it is desirable to prepare a calibration curve in advance according to a conventional method.
  • the measurement reagent of the present invention has a property of being easily taken into cells, and can measure peroxynitrite localized in each cell with high sensitivity by a bioimaging technique.
  • the compound represented by the above general formula (I) or a salt thereof may be used as it is, but if necessary, an additive usually used in the preparation of the reagent may be blended to form a composition. It may be used as an object.
  • additives for using the reagent in a physiological environment additives such as a dissolution aid, a pH adjuster, a buffer, and an isotonic agent can be used. Can be selected.
  • These compositions are provided as a composition in an appropriate form such as a mixture in the form of a powder, a lyophilized product, a granule, a tablet, and a liquid.
  • HPF and APF used in the following examples are compounds described as s s-1F and ss-3F in WO 01/64664, respectively, and were produced according to the method described in the above specification. Was used.
  • Peroxynitrite was prepared according to the method described in the literature (Pryor, WA, et al, Free Rad. Biol. Med. 18, 75-83, 1995). 138 mg (2.06 mmol) of sodium azide was put in a two-necked colben, dissolved by adding 10 mL of water, and the pH was adjusted to 12 by adding a very small amount of a 2N NaOH aqueous solution. When the two-necked kolben was placed in an ice bath and the ozone prepared by the ozone monitor was blown into the aqueous sodium azide solution, the solution became yellow over time.
  • the injection of ozone was stopped, and the resulting solution was dispensed into two test tubes.
  • the test tubes were placed in a dry ice Z acetone bath and frozen to homogeneity. The test tube was allowed to stand at room temperature, and about 500 of the solution in which a part of the frozen material had melted was put into an eppendorf tube to be used as a stock solution of peroxynitrite solution. The concentration of the obtained peroxynitrite solution is ⁇ (Tested from M-m-.
  • Table 1 shows the results.
  • the reagents for measurement (HPF and APF) of the present invention gave an increase in fluorescence upon reaction with peroxynitrite, but did not react with superoxide and NO, and no substantial increase in fluorescence was observed.
  • DCFH gave a strong increase in fluorescence due to the reaction with peroxynitrite, but also gave an increase in the fluorescence due to the reaction with both superoxide and NO. From these results, it is clear that by using the measuring reagent of the present invention, only peroxynitrite can be specifically measured without being affected by superoxide or NO.
  • the reagent for measuring peroxynitrite of the present invention does not react with superoxide and NO, which are precursors of peroxynitrite, and can specifically measure only peroxynitrite. There is.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Physics & Mathematics (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Organic Chemistry (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Réactifs servant à mesurer des péroxynitrites et contenant des composés représentés par la formule (I), par exemple, acide 2-[6-(4'-hydroxy)phénoxy-3H-xanthène-3-one-9-yl] benzoïque et acide 2-[6-(4'-amino)phénoxy-3H-one-9-yl] benzoïque ou ses sels : formule (I) dans laquelle R1 représente amino ou hydroxy, R2 représente 2-carboxyphényle et X1 et X2 représentent chacun indépendamment hydrogène ou halogéno. Ces composés et leurs sels réagissent de façon spécifique avec les péroxynitrites, sans toutefois réagir avec les précurseurs de ces péroxynitrites, à savoir, des superoxydes ou monoxyde d'azote.
PCT/JP2003/013179 2002-10-16 2003-10-15 Reactifs servant a mesurer des peroxynitrites WO2004040296A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP03758728A EP1553409A1 (fr) 2002-10-16 2003-10-15 Reactifs servant a mesurer des peroxynitrites
AU2003275553A AU2003275553A1 (en) 2002-10-16 2003-10-15 Reagents for the measurement of peroxynitrites
US10/531,664 US20060211122A1 (en) 2002-10-16 2003-10-15 Reagents for the measurement of peroxynitrites
JP2004548020A JP4206381B2 (ja) 2002-10-16 2003-10-15 パーオキシナイトライト測定用試薬

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-301291 2002-10-16
JP2002301291 2002-10-16

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WO2004040296A1 true WO2004040296A1 (fr) 2004-05-13

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US (1) US20060211122A1 (fr)
EP (1) EP1553409A1 (fr)
JP (1) JP4206381B2 (fr)
AU (1) AU2003275553A1 (fr)
WO (1) WO2004040296A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7524974B2 (en) 2002-07-08 2009-04-28 Tetsuo Nagano Fluorescent probe
US7541467B2 (en) 2004-01-09 2009-06-02 Shigenobu Yano Fluorescent zinc ion sensor
US7696245B2 (en) 2003-03-28 2010-04-13 Sekisui Medical Co., Ltd. Fluorescent probe for zinc
US7705040B2 (en) 2005-10-07 2010-04-27 The University Of Hong Kong Reagents for highly specific detection of peroxynitrite
WO2014106957A1 (fr) 2013-01-07 2014-07-10 国立大学法人 東京大学 SYNTHÈSE DE RHODAMINE Si ASYMÉTRIQUE ET DE RHODOL

Families Citing this family (5)

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US20110111515A1 (en) * 2008-02-29 2011-05-12 The University Of Tokyo Reagent for measurement of reactive oxygen
JP5067578B2 (ja) * 2008-12-05 2012-11-07 国立大学法人 東京大学 活性窒素測定用試薬
CN104893711B (zh) * 2015-05-20 2017-04-05 浙江大学 检测过氧化亚硝基的荧光探针及制备和应用
CN109608414B (zh) * 2018-12-26 2020-09-29 山东师范大学 检测过氧亚硝酸根的荧光探针及其制备方法和应用
CN110669501B (zh) * 2019-10-25 2023-03-03 南京林业大学 一种对过氧亚硝基阴离子响应的近红外荧光探针及其制备方法和应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7524974B2 (en) 2002-07-08 2009-04-28 Tetsuo Nagano Fluorescent probe
US7696245B2 (en) 2003-03-28 2010-04-13 Sekisui Medical Co., Ltd. Fluorescent probe for zinc
US7541467B2 (en) 2004-01-09 2009-06-02 Shigenobu Yano Fluorescent zinc ion sensor
US7705040B2 (en) 2005-10-07 2010-04-27 The University Of Hong Kong Reagents for highly specific detection of peroxynitrite
WO2014106957A1 (fr) 2013-01-07 2014-07-10 国立大学法人 東京大学 SYNTHÈSE DE RHODAMINE Si ASYMÉTRIQUE ET DE RHODOL
EP3636653A1 (fr) 2013-01-07 2020-04-15 The University of Tokyo Synthèse de rhodamine si asymétrique et de rhodol

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Publication number Publication date
EP1553409A1 (fr) 2005-07-13
AU2003275553A1 (en) 2004-05-25
JPWO2004040296A1 (ja) 2006-03-02
JP4206381B2 (ja) 2009-01-07
US20060211122A1 (en) 2006-09-21

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